tbuckley/cabot-search huggingface dataset:
Management of Menopausal Symptoms
Authors: Carolyn J. Crandall, Jaya M. Mehta, JoAnn E. Manson
Journal: JAMA (2023)

Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM]).Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous thromboembolism associated with CEE (with or without MPA) and breast cancer (with use of CEE plus MPA) is approximately 1 excess event/1000 person-years. Low-dose CEE plus bazedoxifene is not associated with increased risk of breast cancer (0.25%/year vs 0.23%/year with placebo). Bioidentical estrogens approved by the US Food and Drug Administration (with identical chemical structure to naturally produced estrogens, and often administered transdermally) also are available to treat vasomotor symptoms. For women who are not candidates for hormonal treatments, nonhormonal approaches such as citalopram, desvenlafaxine, escitalopram, gabapentin, paroxetine, and venlafaxine are available and are associated with a reduction in frequency of vasomotor symptoms by approximately 40% to 65%. Low-dose vaginal estrogen is associated with subjective improvement in GSM symptom severity by approximately 60% to 80%, with improvement in severity by 40% to 80% for vaginal prasterone, and with improvement in severity by 30% to 50% for oral ospemifene.During the menopausal transition, approximately 50% to 75% of women have vasomotor symptoms and GSM symptoms. Hormonal therapy with estrogen is the first-line therapy for bothersome vasomotor symptoms and GSM symptoms, but nonhormonal medications (such as paroxetine and venlafaxine) also can be effective. Hormone therapy is not indicated for the prevention of cardiovascular disease.
Associations of Prenatal Chemical and Nonchemical Stressors with Early-Adulthood Anxiety and Depressive Symptoms
Authors: Lisa B. Rokoff, Brent A. Coull, Michelle Bosquet Enlow, Susan A. Korrick
Journal: Environmental Health Perspectives (2023)

Background: Prenatal exposure to environmental chemicals may increase risk of childhood internalizing problems, but few studies have explored the potential for longer-term consequences of such exposures. Objective: We evaluated associations between prenatal organochlorine and metal levels and early adulthood internalizing symptoms, considering whether sociodemographic/nonchemical stressors modified these associations. Methods: Participants were 209 young adults, born (1993–1998) to mothers residing in or near New Bedford, Massachusetts. As part of the early-adult assessment, self-reported anxiety (7-item Generalized Anxiety Disorder scale) and depressive (8-item Patient Health Questionnaire) symptoms (≥10: elevated symptoms) were ascertained. We previously analyzed levels of cord serum organochlorines [hexachlorobenzene, dichlorodiphenyldichloroethylene (p,p′-DDE), polychlorinated biphenyls (ΣPCB4: sum of congeners 118, 138, 153, 180)] and whole blood lead shortly after participants' birth, and levels of cord whole blood manganese from archived samples at the time of the adolescent study visit. We used modified Poisson regression models and quantile g-computation, adjusting for sociodemographics, and explored whether biological sex, race/ethnicity (proxy for unmeasured consequences of racism), prenatal social disadvantage (assessed when participants were neonates), and quality of the home environment (assessed during adolescence) modified these associations. Results: Participants were (mean±standard deviation) 22.1±1.5 y old, 76% Non-Hispanic White, and 67% female. Prenatal hexachlorobenzene, p,p′-DDE, and lead exposures were moderately associated with increased risk of elevated anxiety symptoms. There were strata-specific associations for prenatal social disadvantage and quality of home environment such that adverse associations of p,p′-DDE and lead and the overall mixture with anxiety and depressive symptoms were largely only evident in those with lower nonchemical stress [e.g., risk ratio and 95% confidence interval (CI) per doubling p,p′-DDE for anxiety: 1.54 (95% CI: 1.20, 1.99) in high-quality home environments and 0.77 (95% CI: 0.51, 1.16) in low-quality home environments]. Associations between prenatal hexachlorobenzene and p,p′-DDE and anxiety symptoms were stronger for underrepresented racial/ethnic group participants vs. Non-Hispanic Whites. We found minimal evidence for sex-specific effects, and no consistent associations with manganese or ΣPCB4. Discussion: Prenatal organochlorine pesticides and lead exposure possibly increases risk of internalizing problems, particular anxiety symptoms, in young adults. Varying risk was observed by sociodemographic/nonchemical stressor strata, demonstrating the importance of considering interactions between chemical and other stressors. https://doi.org/10.1289/EHP11171
Assessment of Consumer Complaint Investigation Scores, Recertification Survey Scores, and Overall Nursing Home Health Inspection Star Quality Rating
Authors: Lindsay J. Peterson, John R. Bowblis
Journal: JAMA Network Open (2023)

Importance The Centers for Medicare &amp;amp;amp; Medicaid Services’ Five-Star Quality Rating System combines results from nursing home recertification surveys and complaint investigations into a single indicator for health inspections. This combination may mask complaint investigation results. Objective To construct and compare star ratings specific to recertification surveys and specific to complaint investigations to discern whether they provide different information. Design, Setting, and Participants In this quality improvement study, the Nursing Home Compare Five-Star Quality Rating System was used to calculate three 5-star ratings: 1 overall health inspection rating combining recertification survey scores and complaint investigation scores, 1 using only recertification scores, and 1 using only complaint investigation scores. The study included US nursing homes. The sample calculated star ratings for nursing homes in November 2017. This sample included all whose most recent recertification surveys occurred in 2016 up to and including November 2017, and those with 36 months of data from the ASPEN Complaints/Incidents Tracking System and the Certification and Survey Provider Enhanced Reports. Data analyses were completed on different days in 2022, depending on which questions were being addressed. Main Outcomes and Measures Comparison of the 3 star rating distributions. The recertification survey and complaint investigation star ratings were compared with respect to the overall health investigation rating. The recertification and complaint star ratings were cross-tabulated. Results Among the 15 499 nursing homes, 19.8% had 1 overall health inspection star, 23.2% had 2, 23.2% had 3, 23.2% had 4, and 9.8% had 5 overall health inspection stars. Most had the same overall and recertification star ratings; for example, 79.4% had 5 overall stars and 5 recertification survey stars. However, overall and complaint-based star ratings were discordant, with a relatively large proportion of nursing homes (25.7%) having no complaint deficiencies and therefore high star ratings. Conclusions and Relevance In this quality improvement study assessing the 2 components of the Five-Star Quality Rating System, results of recertification surveys were largely similar to health inspection star ratings. However, recertification survey scores differed from complaint inspection scores, suggesting health inspection ratings may not reflect consumers’ views of care, services, or other valued amenities. A complaint-focused metric may have utility. However, research is needed concerning the many nursing homes with no or very few complaint deficiencies.
Manufacturer Spending on Direct-to-Consumer Advertising for Pharmaceutical Products
Authors: Amanda Starc
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat
Authors: Sonata Jodele, Anthony Sabulski
Journal: American Journal of Hematology (2023)

Over the last decade there have been numerous advances in both the diagnosis and treatment of transplant-associated thrombotic microangiopathy (TA-TMA). These are largely the result of an improved understanding of complement activation in TA-TMA and the ability to prevent end organ injury and death with timely initiation of complement-blocking therapies. In this article, we review our current understanding of the pathophysiology of TA-TMA, particularly as it pertains to complement activation, endothelial injury, and clinical management. We then review novel complement-blocking therapies that are currently under investigation for use in TA-TMA, as well as discuss special considerations for complement-blocking therapy in hematopoietic stem cell transplant recipients. Through these reviews we aim to answer or at least provide an educated discussion on the most commonly posed TA-TMA management questions and dilemmas.
Association Between Concussion Burden During Professional American-Style Football and Postcareer Hypertension
Authors: Rachel Grashow, Can Ozan Tan, Saef Izzy, Herman A. Taylor, Marc G. Weisskopf, Meagan M. Wasfy, Alicia J. Whittington, Frank Speizer, Ross Zafonte, Aaron L. Baggish
Journal: Circulation (2023)
Scratching the Surface: NECTIN-4 as a Surrogate for Enfortumab Vedotin Resistance
Authors: David H. Aggen, Carissa E. Chu, Jonathan E. Rosenberg
Journal: Clinical Cancer Research (2023)

Summary Clinical data with enfortumab vedotin (EV) suggest that most bladder cancers overexpress NECTIN-4. A recent article shows that NECTIN-4 membranous expression changes with progression to metastatic disease and that low NECTIN-4 expression in metastatic biopsies is potentially associated with EV resistance. These data argue for incorporation of NECTIN-4 expression into future biomarker strategies. See related article by Klümper et al., p. 1496
Association Between Drug Characteristics and Manufacturer Spending on Direct-to-Consumer Advertising
Authors: Michael J. DiStefano, Jenny M. Markell, Caroline C. Doherty, G. Caleb Alexander, Gerard F. Anderson
Journal: JAMA (2023)

Some drugs are heavily marketed through direct-to-consumer advertising.To identify drug characteristics associated with a greater share of promotional spending on advertising directly to consumers.Exploratory cross-sectional analysis of drug characteristics and promotional spending for the 150 top-selling branded prescription drugs in the US in 2020 as identified from IQVIA National Sales Perspectives data. Promotional spending data were provided by IQVIA ChannelDynamics.Drug characteristics (total 2020 sales; total 2020 promotional spending; clinical benefit ratings; number of indications, off-label use; molecule type; nature of condition treated; administration type; generic availability; US Food and Drug Administration [FDA] approval year, World Health Organization anatomical therapeutic chemical classification; Medicare annual mean spending per beneficiary; percent sales attributable to the drug; market size; market competitiveness) assessed from health technology assessment agencies (France's Haute Autorité de Santé and Canada's Patented Medicine Prices Review Board) and drug data sources (Drugs@FDA, the FDA Purple Book, Lexicomp, Merative Marketscan Research Databases, and Medicare Spending by Drug data).Proportion of total promotional spending allocated to direct-to-consumer-advertising for each drug.The 2020 median proportion of promotional spending allocated to direct-to-consumer advertising was 13.5% (IQR, 1.96%-36.6%); median promotional spending, $20.9 million (IQR, $2.72-$131 million); and median total sales, $1.51 billion (IQR, $0.97-$2.26 billion). Of the 150 best-selling drugs, 16 were missing data and key covariates; therefore, the primary study sample comprised 134 drugs. After adjustment for multiple drug characteristics, the mean proportion of total promotional spending allocated to direct-to-consumer advertising for the remaining 134 drugs was an absolute 14.3% (95% CI, 1.43%-27.2%; P = .03) higher for those with low added clinical benefit than for those with high added clinical benefit and an absolute 1.5% (95% CI, 0.44%-2.56%; P = .005) higher for each 10% increase in total sales.Among top-selling US drugs in 2020, a rating of lower added benefit and higher total drug sales were associated with a higher proportion of manufacturer total promotional spending allocated to direct-to-consumer advertising. Further research is needed to understand the implications of these findings.
TOP-EVs: Technology of Protein delivery through Extracellular Vesicles is a versatile platform for intracellular protein delivery
Authors: Nazma F. Ilahibaks, Arif I. Ardisasmita, Songpu Xie, Anders Gunnarsson, Joseph Brealey, Pieter Vader, Olivier G. de Jong, Saskia de Jager, Niek Dekker, Ben Peacock, Raymond M. Schiffelers, Joost P.G. Sluijter, Zhiyong Lei
Journal: Journal of Controlled Release (2023)

Extracellular vesicles (EVs) have emerged as biocompatible drug delivery vehicles due to their native ability to deliver bioactive cargo to recipient cells. However, the application of EVs as a therapeutic delivery vehicle is hampered by effective methods for endogenously loading target proteins inside EVs and unloading proteins after delivery to recipient cells. Most EV-based engineered loading methods have a limited delivery efficiency owing to their inefficient endosomal escape or cargo release from the intraluminal attachment from the EV membrane. Here, we describe the 'Technology Of Protein delivery through Extracellular Vesicles' (TOP-EVs) as a tool for efficient intracellular delivery of target proteins mediated via EVs. The vesicular stomatitis virus glycoprotein and the rapamycin-heterodimerization of the FKBP12/T82L mutant FRB proteins were both important for the effective protein delivery through TOP-EVs. We showed that TOP-EVs could efficiently deliver Cre recombinase and CRISPR/Cas9 ribonucleoprotein complex in vitro. Moreover, our results demonstrated that the capacity of TOP-EVs to deliver intracellular proteins in recipient cells was not an artifact of plasmid contamination or direct plasmid loading into EVs. Finally, we showed that TOP-EVs could successfully mediate intracellular protein delivery in the liver in vivo. Taken together, TOP-EVs are a versatile platform for efficient intracellular protein delivery in vitro and in vivo, which can be applied to advance the development of protein-based therapeutics.
SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis
Authors: Yongjian Wu, Qiaohua Wang, Miao Li, Juanfeng Lao, Huishu Tang, Siqi Ming, Minhao Wu, Sitang Gong, Linhai Li, Lei Liu, Xi Huang
Journal: Journal of Clinical Investigation (2023)

Uncontrolled inflammation occurred in sepsis results in multiple organ injuries and shock, which contributes to the death of patients with sepsis. However, the regulatory mechanisms that restrict excessive inflammation are still elusive. Here, we identified an Ig-like receptor called signaling lymphocyte activation molecular family 7 (SLAMF7) as a key suppressor of inflammation during sepsis. We found that the expression of SLAMF7 on monocytes/macrophages was significantly elevated in patients with sepsis and in septic mice. SLAMF7 attenuated TLR-dependent MAPK and NF-κB signaling activation in macrophages by cooperating with Src homology 2–containing inositol-5′‑phosphatase 1 (SHIP1). Furthermore, SLAMF7 interacted with SHIP1 and TNF receptor–associated factor 6 (TRAF6) to inhibit K63 ubiquitination of TRAF6. In addition, we found that tyrosine phosphorylation sites within the intracellular domain of SLAMF7 and the phosphatase domain of SHIP1 were indispensable for the interaction between SLAMF7, SHIP1, and TRAF6 and SLAMF7-mediated modulation of cytokine production. Finally, we demonstrated that SLAMF7 protected against lethal sepsis and endotoxemia by downregulating macrophage proinflammatory cytokines and suppressing inflammation-induced organ damage. Taken together, our findings reveal a negative regulatory role of SLAMF7 in polymicrobial sepsis, thus providing sights into the treatment of sepsis.
The novel role of lymphatic vessels in the pathogenesis of ocular diseases
Authors: Thomas Clahsen, Karina Hadrian, Maria Notara, Simona L. Schlereth, Antonia Howaldt, Verena Prokosch, Thomas Volatier, Deniz Hos, Falk Schroedl, Alexandra Kaser-Eichberger, Ludwig M. Heindl, Philipp Steven, Jacobus J. Bosch, Alexander Steinkasserer, Alexander C. Rokohl, Hanhan Liu, Mert Mestanoglu, Hamid Kashkar, Björn Schumacher, Friedemann Kiefer, Stefan Schulte-Merker, Mario Matthaei, Yanhong Hou, Sonja Fassbender, Jonathan Jantsch, Wei Zhang, Philip Enders, Björn Bachmann, Felix Bock, Claus Cursiefen
Journal: Progress in Retinal and Eye Research (2023)
Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation
Authors: Suzanne S. Bohlson, Andrea J. Tenner
Journal: Annual Review of Immunology (2023)

The complement system is an ancient collection of proteolytic cascades with well-described roles in regulation of innate and adaptive immunity. With the convergence of a revolution in complement-directed clinical therapeutics, the discovery of specific complement-associated targetable pathways in the central nervous system, and the development of integrated multi-omic technologies that have all emerged over the last 15 years, precision therapeutic targeting in Alzheimer disease and other neurodegenerative diseases and processes appears to be within reach. As a sensor of tissue distress, the complement system protects the brain from microbial challenge as well as the accumulation of dead and/or damaged molecules and cells. Additional more recently discovered diverse functions of complement make it of paramount importance to design complement-directed neurotherapeutics such that the beneficial roles in neurodevelopment, adult neural plasticity, and neuroprotective functions of the complement system are retained.
Immune Mechanisms in Inflammatory Anemia
Authors: Susan P. Canny, Susana L. Orozco, Natalie K. Thulin, Jessica A. Hamerman
Journal: Annual Review of Immunology (2023)

Maintaining the correct number of healthy red blood cells (RBCs) is critical for proper oxygenation of tissues throughout the body. Therefore, RBC homeostasis is a tightly controlled balance between RBC production and RBC clearance, through the processes of erythropoiesis and macrophage hemophagocytosis, respectively. However, during the inflammation associated with infectious, autoimmune, or inflammatory diseases this homeostatic process is often dysregulated, leading to acute or chronic anemia. In each disease setting, multiple mechanisms typically contribute to the development of inflammatory anemia, impinging on both sides of the RBC production and RBC clearance equation. These mechanisms include both direct and indirect effects of inflammatory cytokines and innate sensing. Here, we focus on common innate and adaptive immune mechanisms that contribute to inflammatory anemias using examples from several diseases, including hemophagocytic lymphohistiocytosis/macrophage activation syndrome, severe malarial anemia during
Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation
Authors: Jianing Fu, Hao Wu
Journal: Annual Review of Immunology (2023)

As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cellular damage and responds by forming the NLRP3 inflammasome, a supramolecular complex that activates caspase-1. The three major components of the NLRP3 inflammasome are NLRP3, which captures the danger signals and recruits downstream molecules; caspase-1, which elicits maturation of the cytokines IL-1β and IL-18 and processing of gasdermin D to mediate cytokine release and pyroptosis; and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which functions as a bridge connecting NLRP3 and caspase-1. In this article, we review the structural information that has been obtained on the NLRP3 inflammasome and its components or subcomplexes, with special focus on the inactive NLRP3 cage, the active NLRP3-NEK7 (NIMA-related kinase 7)-ASC inflammasome disk, and the PYD-PYD and CARD-CARD homotypic filamentous scaffolds of the inflammasome. We further implicate structure-derived mechanisms for the assembly and activation of the NLRP3 inflammasome.
The Questionable Practice of Partialing to Refine Scores on and Inferences About Measures of Psychological Constructs
Authors: Rick H. Hoyle, Donald R. Lynam, Joshua D. Miller, Jolynn Pek
Journal: Annual Review of Clinical Psychology (2023)

Partialing is a statistical approach researchers use with the goal of removing extraneous variance from a variable before examining its association with other variables. Controlling for confounds through analysis of covariance or multiple regression analysis and residualizing variables for use in subsequent analyses are common approaches to partialing in clinical research. Despite its intuitive appeal, partialing is fraught with undesirable consequences when predictors are correlated. After describing effects of partialing on variables, we review analytic approaches commonly used in clinical research to make inferences about the nature and effects of partialed variables. We then use two simulations to show how partialing can distort variables and their relations with other variables. Having concluded that, with rare exception, partialing is ill-advised, we offer recommendations for reducing or eliminating problematic uses of partialing. We conclude that the best alternative to partialing is to define and measure constructs so that it is not needed.